This invention relates to a process for the preparation of 3-bromoanisole by the methoxydenitration of 3-bromonitrobenzene in the presence of a phase transfer catalyst.
3-Bromoanisole (hereinafter indicated also as MBA) is an intermediate in the pharmaceutical field. In particular, it is used for producing the analgesic drug Tramadol.
Among the few known methods for preparing MBA, the most frequently encountered one is that based on the methylation of meta-bromophenol. See, for example, Hewett, J. Chem. Soc. 50 (1936) and Natelson, Gottfried, J. Amer. Chem. Soc. 61, 1001 (1939). Meta-bromophenol in turn is prepared by diazotization starting from meta-bromoaniline or meta-aminophenol. Berti et al., Ann. Chim., 49, 1237, 1248 (1959) reports a method for preparing MBA from meta-anisidine, via a diazotization reaction.
The principal disadvantage of these known processes for the industrial preparation of MBA is that they are based on expensive and insufficiently accessible starting materials. An additional disadvantage consists in the large amounts of aqueous wastes produced in the diazotization process. It is a purpose of this invention to provide a new and convenient route for the preparation of MBA, which starts from 3-bromonitrobenzene, and provides the final MBA in high yield and with good purity.
3-Bromonitrobenzene (hereinafter also designated as BNB) can be prepared by several known routes. Johnson and Gauerke, xe2x80x9cOrganic Synthesisxe2x80x9d, Coll. Vol. 1, 123-124 (1956) examined bromination of nitrobenzene with bromine in the presence of iron powder, at a temperature of 135-145xc2x0 C. The yield of BNB was 60-75%. Several other catalysts were tested by Tronov et al. (Chem. Abstr. 55:8347i and 49:13133d), who obtained 33% BNB by using bromine, sulphuric, nitric and acetic acid at a temperature of 83xc2x0 C. over a period of 4-5 hours, or with bromine and catalysts such as aluminum, sulphur and tellurium. Derbyshire and Waters, J. Chem. Soc., 573-577 (1950) reported that nitrobenzene may be brominated by reaction with hypobromous acid. Bromination of nitrobenzene with potassium bromate was reported in U.S. Pat. No. 4,418,228 and J. Org. Chem., 46, 2169-2171. They claimed that equimolar amounts of bromate and nitrobenzene in 65% sulphuric acid afforded BNB, after 24 hours at 35xc2x0 C., with a yield of 88%. The main deficiency of this method is the need for relatively expensive and technically difficult to use, alkali metal bromate.
Thus, another purpose of this invention is to provide a new and convenient route for the preparation of BNB, by the bromination of nitrobenzene with bromine in oleum to overcome the problems connected with the use of alkali metal bromate.
Other purposes and advantages of the invention will better appear as the description proceeds.
The invention provides a process for the preparation of 3-bromoanisole comprising methoxydenitrating 3-bromonitrobenzene in the presence of a phase-transfer catalyst (PTC), and the preparation of 3-bromonitrobenzene by the bromination of nitrobenzene with bromine in oleum.
In one aspect, the invention is directed to a process for the preparation of 3-bromoanisole comprising methoxydenitrating 3-bromonitrobenzene in the presence of a phase-transfer catalyst. According to a preferred embodiment of the invention, the methoxydenitration reagent is an alkali metal methoxide. Preferably, the alkali metal methoxide is selected from sodium methoxide and potassium methoxide.
According to a preferred embodiment of the invention, the amount of methoxide used is 1-1.5 mol per mol of 3-bromonitrobenzene. The alkali methoxide can be a pre-prepared solid or it can be prepared in situ, by the reaction of the corresponding alkali hydroxide and methanol. Typically, in the case when pre-prepared solid methoxide is used, the effective amount of alkali hydroxide is between 1.2-1.7 mol per mol of 3-bromonitrobenzene. Typical reaction temperatures are between about 40 to 80xc2x0 C. Preferred reaction temperatures are between 50 to 55xc2x0 C.
In the case in which methoxide is prepared in situ, the effective amount of alkali hydroxide is between 2.2-2.4 mol per mol of 3-bromonitrobenzene. Typical reaction temperatures are between about 50 to 80xc2x0 C. Preferred reaction temperatures are between about 55 to 65xc2x0 C.
The concentration of phase transfer catalyst can be easily selected by the skilled chemist for specific reaction conditions. Illustrativexe2x80x94but non-limitative concentrations of phase transfer catalyst are in the range of 20 to 30 wt % relative to the initial BNB. Examples of suitable phase transfer catalysts include tributylmethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, or tetrabutylammonium bromide. Other suitable PTCs will be easily recognized by the skilled person.
In another aspect the invention relates to a process for the preparation of 3-bromonitrobenzene, comprising reacting nitrobenzene with bromine in oleum as the reaction medium. Optionally, the reaction can be carried out in the presence of iodine. Small amounts of iodine, e.g., amounts of up to 5% by weight relative to the substrate are usually sufficient. Preferred (but non-limitative) iodine contents are in the rang 0-5% weight % relative to the nitrobenzene, more preferably about 0.2-0.5 weight %. Iodine acts in this process as a catalyst and, therefore, low amounts of iodine are sufficient.
The oleum contains free SO3. The content of free SO3 in the oleum is typically about 1-65%. According to a preferred embodiment of the invention, however, the oleum contains about 15-30% free SO3.
Typical reaction temperatures are between about 0-100xc2x0. According to a preferred embodiment of the invention the reaction temperature is between about 20-40xc2x0 C.
The oleum/nitrobenzene weight ratio may vary, and is typically between about 1.5 and 10.
According to a preferred embodiment of the invention the Br2/nitrobenzene molar ratio is in the range of 0.3 to 1, more preferably in the range of 0.4 to 0.5.
According to a preferred embodiment of the invention the bromination mixture is further processed by one of the following procedures:
Procedure A:
a) diluting with water; and
b) phase separation at a temperature above 50xc2x0 C.
Procedure B:
a) diluting with water; and
b) cooling and filtering the crystallized 3-bromonitrobenzene.
Procedure C:
a) diluting with water;
b) extracting the 3-bromonitrobenzene with an organic solvent; and
c) phase separation. Various different solvents can be employed in the reaction of the invention, as will be easily understood by the skilled person. Illustrative suitable solvents include dichloroethane, dichloromethane, toluene, xylene or cyclohexane.
In still another aspect the invention encompasses a process for the preparation of 3-bromoanisole, comprising the steps of:
a) preparing 3-bromonitrobenzene by reacting nitrobenzene with bromine in oleum as the reaction medium.
b)preparing 3-bromanisole from said 3-bromonitrobenzene by methoxydenitrating 3-bromonitrobenzene in the presence of a phase-transfer catalyst (PTC).
All the above and other characteristics and advantages of the invention will be better understood through the following illustrative and non-limitative detailed description of preferred embodiments thereof.
BNB is prepared by a new process, comprising reacting nitrobenzene with bromine, in oleum, optionally in the presence of iodine.
According to a preferred embodiment of the invention, the oleun contains about 1-65% free SO3. Preferably, but non-limitatively, the oleum contains about 15-30% free SO3.
While a broad range of iodine contents is permissible, according to a preferred embodiment of the invention, iodine is present in an amount of about 0-5 wt % relative to nitrobenzene, preferably but not Imitatively 0.2-0.5 wt % relative to the nitrobenzene.
As will be apparent to a person skilled in the art, the process of the invention can proceed in a very broad range of temperatures. According to a preferred embodiment of the invention, however, the reaction temperature is kept between about 0-100xc2x0 C., and more preferably, 20-40xc2x0 C.
The oleum/nitrobenzene weight ratio can vary within a broad range. According to a preferred embodiment of the invention, however, the oleum/nitrobenzene weight ratio is between about 1.5 and 10.
The Br2/nitrobenzene molar ratio is also variable within a broad range, typically in the range of 0.3-1.0. According to a preferred embodiment of the invention, the Br2/nitrobenzene molar ratio is in the range of 0.4-0.5.
The working-up of the bromination mixture may be carried out by several methods:
a) Dilution with water followed by phase separation at a temperature above 50xc2x0 C.
b) Dilution with water, cooling and filtering of the crystallized, crude BNB.
c) Dilution with water, followed by extraction of the crude BNB with an organic solvent (dichloroethane, dichloromethane, toluene, xylene, cyclohexane, etc.) and phase separation. A variation of this may be extraction without previous dilution. In this case, part of the used oleum may be returned to the next bromination, after make-up with oleum, 65% free SO3 oleum.
The purification of the crude BNB may be carried out by distillation or by crystallization from methanol, ethanol, isopropanol, etc.
BNB was obtained with a yield of xcx9c80%, based on reacted nitrobenzene, and a purity of 98-99% after distillation.
3-Bromoanisole is prepared by nucleophilic substitution of the nitrate group in BNB. The methoxydenitration of BNB is carried out by its reaction with alkali metal methoxide such as sodium methoxide or potassium methoxide, employing an effective amount of a phase transfer catalyst (PTC), in a medium of a water-immiscible nonpolar aprotic solvent, such as cyclohexane, hexane, heptane, octane, nonane, xylenes, and preferably, toluene.
An effective amount of PTC is employed in a range of from 20 to 30% w/w, based on the initial BNB. The PTC is selected from quaternary ammonium salts. Especially suitable phase transfer catalysts are tributylmethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, and in particular, tetrabutylammonium bromide.
Two different methods of employing the alkali metal methoxide are suggested. The first method consists in using pre-prepared solid alkali metal methoxide. The reaction is carried out using sodium or potassium methoxide, with sodium methoxide being preferred, in the presence of an effective amount of potassium hydroxide. The amount of methoxide used is 1.1-1.2 mol, based on 1 mol BNB. An effective amount of potassium hydroxide is comprised of between 1.2-1.7 mol, and preferably 1.4-1.7 mol with respect to 1 mol BNB. Said reaction is carried out at a temperature of between 40 and 80xc2x0 C., and preferably between 50 and 55xc2x0 C.
The second method of carrying out the methoxydenitration employs potassium methoxide prepared in situ, in the course of the reaction, from methanol and potassium hydroxide. The amount of methanol used is 1.1-1.2 mol, based on 1 mol BNB. The amount of potassium hydroxide is comprised between 2-2.4 mol, and preferably between 2.2-2.4 mol, with respect to 1 mol BNB. Said reaction is carried out at a temperature of between 50 and 80xc2x0 C., and preferably between 55 and 65xc2x0 C.
The reaction may also be performed with sodium methoxide prepared in situ from methanol and sodium hydroxide. However, sodium methoxide so prepared is considerably less reactive than potassium methoxide.
In both methods, some water may optionally be added to the starting reaction mixture, in order to partially dissolve the solid potassium hydroxide , and thus to facilitate stirring of the heterogeneous mixture.
The reaction should be performed under aerobic conditions in order to suppress the radical processes leading to the formation of products of nitro reduction, mainly hydrodebromination to nitrobenzene and nitro reduction to 3,3xe2x80x2-dibromoazoxybenzene and 3,3xe2x80x2-dibromoazobenzene.
The crude MBA so obtained is purified by means of fractional distillation. The fractional distillation may be carried out in the presence of an alkali such as sodium hydroxide or potassium hydroxide, as will be described hereinafter.
The processes according to the invention provide 3-bromonitrobenzene and 3-bromoanisole in good yields and with high purity.